Neisseria meningitidis and Neisseria gonorrhoeae are important human pathogens. N. meningitidis causes meningitis, sepsis and bacteremia; N. gonorrhoeae causes gonorrhoea in both sexes, pelvic inflammatory disease and/or sterility in women, and rectal and pharyngeal infections, as in homosexual men. More rarely, disseminated gonococcal infection (gonococcal bacteremia) can result, with complications such as polyarthralgias or purulent arthritis, for example. These two species are relatively closely related genetically; there is approximately 85% DNA sequence homology between the genomes of the two species. The genus also includes several other species which are nonpathogenic to man although they colonize the upper respiratory tract.
The capsule of N. meningitidis contains N-acetylneuraminic acid (sialic acid) polymerized in .alpha.2-8 linkage; the capsule is a component which contributes to virulence in that it appears to offer at least some protection against the bactericidal activity of serum and it appears to promote invasiveness. The Group B capsule is poorly antigenic because it mimics the neural cell adhesion molecule (NCAM) . It also down regulates the activation of the alternative complement pathway by enhanced binding of the complement factor II to cell surface-deposited C3b, which is subsequently inactivated by Factor I. The level of Group B capsule expression affects the virulence of the meningococci in the mouse model and the attachment of the meningococcal cells to mucosal surfaces. N. gonorrhoeae is not encapsulated, but extracellular polyphosphate is produced.
Neisseria produce lipopolysaccharide (LPS) which is associated with the bacterial outer membrane. The lipopolysaccharide differs from that of the Enterobacteriaceae in that there are short, often branched sugar chains rather than relatively long repeating subunits. Hence, the neisserial LPS is known as lipooligosaccharide (LOS). Neisserial LOS is classified into six serotypes among the gonococci and into thirteen in the meningococci. Neisserial LOS contain glucose, galactose, 3-keto-2-deoxyoctanoic acid (KDO), glucosamine, galactosamine, sialic acid and ethanolamine in ratios and linkages which depend on the serotype. LOS molecules generally have molecular masses in the range of about 3200 to about 7000, as estimated by sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS PAGE). The short, often branched oligosaccharide chains are attached via KDO to lipid A embedded in the outer membrane. The LOS structure of a particular strain is subject to antigenic variation.
The lipid A acts as a classic endotoxin and can induce changes in the permeability of the blood brain barrier after invasion of the cerebrospinal fluid during meningococcemia [Tunkel and Scheld (1993) Clin. Res. Microbiol. 6:118-136]. The composition of the LOS influences the invasive capacity of the meningococci [MacKinnon et al. (1993) Microb. Path. 15:359-366] and in the gonococci as well as the meningococci, the composition of the LOS affects the susceptibility of the bacterial cells to normal human serum [Shafer et al. (1984) J. Infec. Dis. 149:179-183; Porat et al. (1995) Infect. Immun. 63:2164-2172].
The terminal galactose of neisserial lipooligosaccharide is sialylated. The wild-type LOS lacto-N-tetraose unit of eight of the twelve serotypes of N. meningitidis appears to mimic certain human blood group antigens [Mandrell et al. (1988) J. Exp. Med. 168:107-126; Tsai and Civin (1991) Infect. Immun. 59:364-369]. Phase variation can produce heterogeneous oligosaccharide chains, and therefore a change in the antigenic profile of the strains. In gonococci, attachment of the sialic acid to the terminal galactose found in many of the LOS immunotypes results in increased resistance to the bactericidal action of normal human serum. Accordingly, in the formulation of vaccine compositions, it is important to avoid triggering an autoimmune response in the vaccinated individual.
While purified polysaccharides from Groups A and C meningococci have been used successfully in vaccines, the polysaccharides of the Group B meningococci are poor antigens, per Davis et al. (1990) Microbiology and Immunology, J. B. Lippincott Company, Philadelphia, Pa., at page 558.
There is a long felt need in the art for a protective vaccine effective in the prevention of human diseases caused by the pathogenic Neisseria species, N. gonorrhoeae and N. meningitidis, especially Group B meningococci. Meningococcal meningitis or meningococcemia can result in about 85% mortality if untreated and about 10-20% if treated, and those with deficiencies in late complement cascade components C5, C6, C7 and C8 appear to be prone to multiple episodes of meningococcal meningitidis. For example, nonpathogenic strains or antigenic material therefrom, particularly those which lack intact lipooligosaccharide (LOS) structure, as antigen for preparing antibodies specific to this bacterial surface component or for vaccines useful in protection against the neisserial disease resulting from infection with Neisseria species.